5-oxo-1,2,3,4-tetrahydro-5h-(1)benzopyrano(3,4-c)pyridines



United States Patent Oflice 3,514,464 Patented May 26, 1970 US. Cl.260295 7 Claims ABSTRACT OF THE DISCLOSURE A new series of 5 oxo l,2,3,4tetrahydro 5H- [l]benzopyrano[3,4 c]pyridines used as intermediates inthe preparation of l,2,3,4-tetrahydro-5H[l] benzopyrano[3,4-c]pyridinesand 5H [1]benzopyranol[3,4-c] piperidines which have CNS. andcardiovascular activity.

This invention relates to novel chemical compositions of matter known inthe art of chemistry as 1,2,3,4-tetrahydro 5H[l]benzopyrano[3,4-c]pyridines and 5H- [l]benzopyran0[3,4-c]-piperidineshaving the Formulas la, b and Ila, b, respectively:

2 R N3 1 R -N 3- l4 0 (l a and to 5 oxo 1,2,3,4tetrahydro-SH-[l]benzopyrano [3,4-c1pyridines, useful as intermediatesfor the preparation of the compounds of Formulas Ia, b and Ila, b, andhaving the Formulas HIa, b:

R N s W OH R2 V l l (IIIa) (1111)) In the compounds of Formulas la, b;IIa, b; and Illa, b above, R is lower-alkyl; R is methyl or 3-methyl-2-octyl; R is a member of the group consisting of hydrogen, lower alkyl,lower-alkanoyl, cycloalkyl-lower-alkyl, cycloalkyl-lower-alkanoyl,lower-alkenyl, lower-alkynyl, halo-lower-alkenyl (including fluoro-,chloro-, -bromo-, and iodo-lower-alkenyl), phenyl-lower-alkyl,phenyl-lower-alkanoyl, phenyl-loWer-alkenyl, and phenyl-lower-alkynyl;and R is hydrogen, lower alkyl, lower-alkanoyl, carbamyl,N-lower-alkylcarbamyl, N,N di lower-alkylcarbamyl, or phosphonyl, Rbeing methyl only when R is hydrogen, lower alkanoyl, cycloalkyl-loweralkyl, cycloalkyl lower-alkanol, lower-alkenyl, lower-alkynyl,halolower-alkenyl, phenyl-lower-alkyl, phenyl-lower-alkanoyl,phenyl-lower alkenyl, or phenyl-lower-alkenyl.

As used herein, the term lower-alkyl means saturated, monovalentaliphatic radicals, including straight or branched chain radicals offrom one to six carbon atoms, as illustrated by, but limited to methyl,ethyl, propyl, isopropyl, butyl, sec-butyl, amyl, hexyl, and the like.

As used herein, the term lower-alkenyl means monovalent, aliphaticradicals of fro-m three to seven carbon atoms which contain at least onedouble bond, and are either straight or branched-chain, as illustratedby, but not limited to l-(2-propeny1), 1-(3-methyl-2-propenyl),1-(1,3-dimethyl-2-propenyl), 1-(2-hexenyl), and the like.

As used herein, the term loWer-alkyny means monovalent, aliphaticradicals, of from three to seven carbon atoms which contain at least onetriple bond, and are either straight or branched-chain, as illustratedby, but not limited to l-(2-propynyl), l-(l-methyl-Z-propynyl),1-(2-heptynyl), and the like.

As used herein, the term cycloalky means cyclic, saturated aliphaticradicals of from three to eight carbon atoms, as illustrated by, but notlimited to cyclopropyl, cyclobutyl, Z-methylcyclobutyl, cyclohexyl, 4-rnethylcyclohexyl, cyclooctyl, and the like.

As used herein, the term lower-alkanoyl means saturated, monovalent,aliphatic radicals derived from a mono-carboxylic acid, includingstraight or branchedchain radicals of from one to six carbon atoms, asillus trated by, but not limited to formyl, acetyl, propionyl,

u-methylpropionyl, butyryl, hexanoyl, and the like As used herein, theterms phenyl-lower-alkyl, phenyllower-alkanoyl, phenyl-lower-alkenyl,and phenyllower alkynyl mean a monovalent radical consisting of a phenylnucleus bonded to the rest of the molecule through, respectively, adivalent lower-alkylene radical of from one to four carbon atoms asillustrated by, but not limited to methylene, 1,1-ethylene,1,2-ethylene, 1,3-propy1ene, 1,2- propylene, 1,4-butylene and the likeor through a divalent lower-alkenylene radical of from two or fourcarbon atoms, as illustrated by, but not limited to 1,2-ethenylene,1,3-(1-propenylene), 1,3-(l-butenylene), 1,4-(2-butenylene), and thelike, or through a divalent lower-alkynylene radical of from two to fourcarbon atoms, as illustrated by but not limited to 1,2-ethyny1ene,1,3-propynylene, 1,3-(1- butynylene), and the like. Here and elsewherethroughout this specification, it will be understood the benzene ring ofphenyl can bear any number and kind of substituents such as would occurto the man skilled in the organic chemistry. Solely for illustration,and without limitation, such substiuents include lower-alkyl,lower-alkoxy, halo(chloro, bromo, iodo, or fluoro), nitro,lower-alkylmercapto, and the like.

The compounds of Formulas Ia, b where R, is hydrogen are prepared byreacting an 8 alkyl-IO-hydroxy-S- oxo l,2,3,4-tetrahydro 5H[l]benzopyrano[3,4-c] pyridine or a 10 alkyl 8hydroxy-S-oxo-l,2,3,4-tetrahydro-5-H-[l]benzopyrano[3,4-c1pyridine,having the respective Formulas 111a and IIIb, with a lower-alkylmagnesium halide as illustrated by the equation:

where R R and R have the meanings given hereinabove, and Hal representshalogen. The reaction is carried out in an organic solvent inert underthe conditions of the reaction. Suitable solvents are diethyl ether,dibutyl ether, tetrahydrofuran, anisole, pyridine, and the like. It ispreferred to add a solution of the 8-alkyl-10-hydroxy- 5 oxo 1,2,3,4tetrahydro-5H-[1]benzopyrano[3,4-c] pyridine or alkyl 8hydroxy-S-oxo-1,2,3,4-tetrahydro 5H [l]benzopyrano[3,4-c])pyridine in apyridine or anisole solution, or in a mixture of these solvents, to asolution of the Grignard reagent in anisole.

The compounds of Formulas IIIa, b in turn are prepared by reacting a 1-R-3 carbo-lower-alkoxy-4-piperidone of Formula IV with aS-alkylresorcinol of Formula V. The reaction is carried out in a mixtureof concentrated sulfuric acid and phosphorus oxychloride or in thepresence of other acidic condensation agents such as aluminum chloride,hydrogen chloride, or polyphosphoric acid and is illustrated by theequation:

l l o=L R2 It -N --O HO- R2 boom; l (IV) (V) (IIIb) where R and R aredefined as above, and Alk is loweralkyl.

As indicated by the reaction scheme above, the ring closure of the l-R-3-carbo-lower-alkoxy-4-piperidone with the S-alkylresorcinol can takeplace either by cyclization at the 2-position of the S-alkylresorcinol,as indicated by the arrow (a), to produce the 8 alkyl 10- hydroxy-S- 0x0l,2,3,4 tetrahydro-SH-[1]benzopyrano[3,4-c]pyridines of Formula IIIa' orby cyclization at the 4-position of the S-alkylresorcinol, as indicatedby the arrow (b), to produce the10-alkyl-8-hydroxy-5-oxo-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c1pyridinesof Formula IIIb. Generally either the compounds of Formula 11111 or ofFormula IIIb are produced by either S-methylresorcinol (R is CH or by 5(3 methyl-2-octyl)resorcinol (R is CHCH CHCH C H but in the latter case,the predominant products are the compounds of Formula IIIa :owing to thepartial steric hindrance of the 4-position of the resorcinol by therather bulky 3-methyl-2-octyl group in the adjacent 5-position whichinhibits cyclization at the 4-position.

The intermediate S-methyland 5-(3-methyl-2-octyl)- resorcinols ofFormula V are known in the art.

The intermediate 1-R -carbo-lower-alkoxy-4-piperidones of Formula IV areprepared by the method of Prill and McElvain, J. Am. Chem. Soc. 55,1233(1933) and of McElvain and Vozza, J. Am. Chem. Soc. 71, 896(1948).

The compounds of Formulas Ia and lb where R is hydrogen are alsoadvantageously prepared by catalytically 'debenzylating, with hydrogenin the presence of a catalyst, the com-pounds of Formulas la, bhereinabove where R is benzyl. The reaction is preferably carried out inan organic solvent inert under the conditions of the reaction, forexample methanol, ethanol, isopropanol, and the like. Suitable catalystsare platinum or palladium-on-charcoal. A preferred catalyst ispalladium-on-charcoal.

The compounds of Formulas la, b or IIa, b, where R iscyc1oalkyl-lower-alkyl, lower-alkenyl, lower-alkynyl,halo-loWer-alkenyl, phenyl-loWer-alkyl, phenyl-loweralkenyl, orphenyl-lower-alkynyl are prepared by reacting the correspondingcompounds of Formulas la, b or Ila, b, where R is hydrogen with acycloalkyl-lower-alkyl, lower-alkenyl, lower-alkynyl, halo-loweralkenyl, phenyllower-alkyl, phenyl-lower-alkenyl, or phenyl-loweralkynylhalide, respectively. The reaction is preferably carried out in anorganic solvent inert under the conditions of the reaction, for examplemethanol, ethanol, isopropanol, or dimethylformamide, and in thepresence of an acid-acceptor. The purpose of the acid-acceptor is totake up the hydrogen halide split out during the course of the reactionand is a basic substance which forms water-soluble salts readilyseparable from the reaction mixture. Suitable acid-acceptors are alkalimetal carbonates or bicarbonates, for example sodium or potassiumcarbonate, or bicarbonate, or alkali metal hydroxides, for examplesodium or potassium hydroxide. The reaction can also be carried out inthe presence of a molar excess of the bases of Formulas la, b or Ila, bwhere R is hydrogen. A preferred acid-acceptor is sodium carbonate, anda preferred solvent is ethanol.

The compounds of Formulas Ia, b or Ila, b where R is lower-alkanoyl,cycloalkyl-lower-alkanoyl, or phenyllower-alkanoyl are prepared byreacting the corresponding compounds of Formulas la, b or IIa, b whereR, is hydrogen with an acid halide or anhydride of a loweralkanoic,cycloalkyl-lower-alkanoic, or phenyl-loweralkanoic acid, respectively.The reaction is preferably carried out in an organic solvent inert underthe conditions of the reaction, for example benzene, toluene, xylene,and the like, and in the presence of a basic catalyst, for examplepyridine, triethylamine, dimethylaniline, and the like. A preferredsolvent is benzene, and a preferred basic catalyst is pyridine.

The compounds of Formulas Ia, b or Ila, b where R iscycloalkyl-lower-alkyl and phenyl-lower-alkyl can also be prepared byreducing, with an alkali metal aluminum hydride, the compounds ofFormulas la, b or Ila, b where R is cycloalkyl-lower-alkanoyl orphenyl-lower-alkanoyl, respectively, and where R, is hydrogen orlower-alkyl.

The reaction is preferably carried out in an organic solvent inert underthe conditions of the reaction, for example diethyl ether,tetrahydrofuran, dibutyl ether, and the like.

The 8-alkyl-10-hydroxy-S,5-di-lower-alkyl-5H-[l]benz0-pyrano[3,4-c]piperidines and 10-alkyl-8-hydroxy-5,5-dilower alkyl H-[l]benzopyrano[3,4c]piperidines of Formulas Ila and 11b, respectively,are prepared by reducing with hydrogen over a suitable catalyst the 8alkyl hydroxy 5,5di-lower-alkyl-l,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridines and10-alkyl- 8 hydroxy 5,5 di lower alkyl-l,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridines of Formulas Ia and lb, respectively,where R R and R have the meanings given above and R is hydrogen,lower-alkyl, loweralkanoyl, cycloalkyl-lower-alkyl,cycloalkyl-lower-alkanoyl, phenyl-lower-alkanoyl, or phenyl-lower-alkyl.The reaction is carried out in an organic solvent inert under theconditions of the reaction, for example methanol, ethanol, isopropanol,and the like. Suitable catalysts include palladium-on-charcoal,platinum, Raney nickel, and the like. A preferred catalyst is Raneynickel.

The ester and ether derivatives of the compounds of Formulas la, b andIla, b, that is the compounds where R, is lower-alkyl, lower-alkanoyl,carbamyl, N-loweralkylcarbamyl, N,N-di-lower-alkylcarbamyl, orphosphonyl are prepared by reacting the corresponding compounds where R;is hydrogen, preferably in the presence of a basic catalyst, with alower-alkyl halide, to produce the compounds where R, is lower-alkyl;with a lowerankanoic anhydride (or mixed anhydride), to produce thecompounds where R, is loWer-alkanoyl; with a molar equivalent ofphosgene followed by reaction of the resulting chloroformate withammonia, a lower-alkylamine, or a di-lower-alkylamine, to produce thecompounds where R, is, respectively, carbamyl, N-lower-alkylcarbamyl, orN,N-di-lower-alkylcarbamyl; or with one molar equivalent amount ofphosphorus oxychloride followed by reaction of the resultingdichlorophosphinate with aqueous sodium or potassium carbonate, toproduce the compounds where R, is phosphonyl. Suitable solvents arebenzene, toluene, xylene, and the like, and suitable basic catalysts arealkali metal carbonates, bicarbonates, or hydroxides, dimethylaniline,pyridine, and the like.

The acid-addition salts of the bases herein described are the form inwhich the bases are most conveniently prepared for use and are the fullequivalents of the subject matter specifically claimed. The acidmoieties or anions in these salt forms are in themselves neither novelnor critical and therefore can be any acid anion or acid-like substancecapable of salt formation with the free base form of the compounds. Thepreferred type of salts are water-soluble pharmacologically-acceptablesalts, that is, salts whose anions are relatively innocuous to theanimal organisms in pharmacological doses of the salts, so that thebeneficial physiological properties inherent in the free base are notvitiated by side effects ascribable to the anions; in other words, thelatter do not substantially affect the pharmacological propertiesinherent in the cations. In practicing the invention, it has been foundconvenient to form the hydrochloride salt. However, other appropriatepharmacologically-acceptable salts within the scope of the invention arethose derived from mineral acids such as hydrobromic acid, hydriodicacid, nitric acid, phosphoric acid, sulfamic acid, and sulfuric acid;and organic acids such as acetic acid, citric acid, tartaric acid,lactic acid, methanesulfonic acid, ethanesulfonic acid, quinic acid, andthe like, giving the hydrobromide, hydriodide, nitrate, phosphate,sulfamate, sulfate, acetate, citrate, tartrate, lactate,methanesulfonate, ethanesulfonate, and quinate, respectively.

Although pharmacologically-acceptable salts are preferred, those havingtoxic anions are also useful. All acidaddition salts are usefulintermediates as sources of the free base form even if the particularsalt per se is not 6 desired as the final product, as for example whenthe salt is formed only for purposes of purification or identification,or when it is used as an intermediate in preparing apharmacologically-acceptable salt of ion-exchanging procedures.

The compounds of Formulas la, b and Ila, b have been shown to possessCNS. and cardiovascular activity as evidenced by gross overt changesinduced by intravenous administration in mice in standard testsinvolving observations of psychomotor activity, reactivity to stimuli,and ability to perform normal, non-conditioned motor tasks. Thisactivity indicates their usefulness as psychotropic agents.

The compounds can be prepared for use by dissolving under sterileconditions a salt form of the compounds in water (or an equivalentamount of a non-toxic acid if the free base is used), or in aphysiologically compatible aqueous medium such as saline, and stored inampoules for intramuscular injection. Alternatively, they can beincorporated in unit dosage form as tablets or capsules for oraladministration either alone or in combination with suitable adjuvantssuch as calcium carbonate, starch, lactose, talc, magnesium stearate,gum acacia, and the like. Still further, the compounds can be formulatedfor oral administration in aqueous alcohol, glycol, or oil solutions oroil-water emulsions in the same manner as conventional medicinalsubstances are prepared.

The molecular structures of the compounds of our invention were assignedon the basis of study of their infrared, ultraviolet, and NMR spectraand their transformation products, and confirmed by the correspondencebetween calculated and found values for the elementary analyses forrepresentative examples.

The following examples will further illustrate the invention without,however, limiting it thereto.

EXAMPLE 1 l O-hydroxy-S- 3-methyl-2-octyl) -3,5 ,5 -trimethyl- 1 ,2,3,4-tetrahydro-5H-[ 1 ]-benzopyrano [3 ,4-c] pyridine (A) 10 hydroxy 5 oxo 3methyl 8 (3 methyl 2 octyl) 1,2,3,4 tetrahydro 5H [1]benzopyrano[3,4-c1pyridine. 1 methyl 3 carbethoxy 4 piperidone hydrochloride, (42g., 0.19 mole) was added in portions to 27.8 g. (0.12 mole) of5-(3-methyl-2-octyl) resorcinol with stirring, and 48 ml. ofconcentrated sulfuric acid was then added dropwise to the mixture atroom temperature. The mixture was then treated with 21 ml. of phosphorusoxychloride, stirred at room temperature for seventy-eight hours,neutralized with aqueous potassium bicarbonate, and the productextracted into chloroform. The organic extracts were washed first withbicarbonate solution and then with water, dried over anhydrous sodiumsulfate, and taken to dryness. The crude product (44 g.) was extractedwith five 350 ml. portions of boiling acetonitrile, and from the fifthextract there was obtained 7.3 g. ofl0-hydrovy-5-oxo-3-methyl-8-(3-methyl 2 octyl) 1,2,3,4 tetrahydro 5H[l]benzopyrano [3,4-c]pyridine, M.P. 169,173 C.

(B) 10 hydroxy 8 (3 methyl 2 octyl) 3,5,5- trimethyl l,2,3,4 tetrahydro5H [l]benzopyrano [3,4-c]pyridine.A solution of 3.5 g. (0.01 mole) of10- hydroxy 5 oxo 3 methyl 8 (3 methyl 2 octyl)- 1,2,3,4 tetrahydro 5H[1]benzopyrano[3,4-c]pyridine, dissolved in ml. of pyridine, was addeddropwise to a solution of 0.1 mole of methyl magnesium iodide in ml. ofanisole. When addition was complete, the mixture was stirred at 30-45"C. for about eight hours, cooled, and the excess Grignard reagentdecomposed with 100 ml. of Water. The mixture was then acidified with300 ml. of 4 N sulfuric acid, and steam distilled to remove the anisole.The aqueous residue was then basified by the addition of solid sodiumcarbonate, and the pyridine removed by steam distillation. The solidwhich separated from the cooled reaction mixture was collected and driedgiving 3.36 g. of the product in free base form. The latter wasconverted to the hydrochloride salt in ethyl acetate and recrystallizedfrom acetonitrile giving 1.4 g. of 10 hydroxy 8 (3 methyl 2 octyl) 3,5,5trimethyl 1,2,3,4 tetrahydro 5H [1]benzopyrano[3,4- c] pyridinehydrochloride, M.P. 28l293 C.

Analysis.--Calcd. for C H NO .HCl (percent): C, 70.65; H, 9.39; N, 3.43.Found (percent): C, 71.07; H, 9.45; N, 3.42.

EXAMPLE 2 5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-1,2,3,4-tetrahydro-SH- 1 benzopyrano 3,4-c] pyridine (A) 3 benzyl 10 hydroxy 8(3 methyl 2- octyl) 5 oxo 1,2,3,4 tetrahydro 5H [1]benzopyrano[3,4-c]pyridine hydrochloride. 1 benzyl 3- carbethoxy 4 piperidonehydrochloride, (11 g., 0.037 mole) was added in portions to 10.2 g.(0.041 mole) of 5-(3-methyl-2-octyl)resorcinol with stirring, and themixture was then treated dropwise with cooling with 22 ml. ofconcentrated sulfuric acid. When addition was complete, 6 ml. ofphosphorus oxychloride was added all at once, and the mixture stirredfor sixteen hours at room temperature. Isolation of the product in theform of its hydrochloride salt and recrystallization from acetonitrilegave 6.5 g. of 3-benzyl-l0-hydroxy-8-(3-methy1-2-octyl)- 5 oxo 1,2,3,4tetrahydro 5H [1]benzopyrano[3, 4-c] pyridine hydrochlaoride, 'M.P.236240 C.

Analysis.-Calcd. for C H NO .HC1 (percent): C, 71.55; H, 7.50; N, 2.97.Found (percent): C, 71.29; H, 7.74; N, 2.96.

(B) 3-benzyl-5,5-dimethyl-l0-hydroxy 8 (3-meth'yl-2-octyl)-1,2,3,4-tetrahydro 5H [1]benzopyrano[3,4-c] pyridinehydrochloride was prepared from 11.5 g. (0.026 mole) of 3benzyl-l-hydroxy-8-(3-methyl-2-octyl)-,5- oxo 1,2,3,4tetrahydro-H-[1]benzopyrano[3,4-c]pyridine hydrochloride and 0.24 moleof methyl magnesium iodide in anisole using the procedure describedabove in Example l-B. The crude product, isolated in the form of thehydrochloride salt, was recrystallized from ethyl acetate giving 2.9 g.of 3-benzyl-5,5-dimethyl-10-hydroxy-8- (Ii-methyl 2octyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridinehydrochloride, M.P. 149-152 C.

Analysis.Ca1cd. for C H NO .HCI (percent): C, 74.43; H. 8.74; N, 2.89.Found (percent): C, 73.56; H, 8.89; N, 2.83.

(C) 5,,5-dimethyl 10 hydroxy-8-(3-methyl-2-octyl)- 1,2,3,4 tetrahydro SH[1]benzopyrano[3,4-c]pyridine.A solution of 10 g. (0.024 mole) of3-benzyl-5,5- dimet'hyl-l0-hydroxy-8-(3-methyl 2 octyl) 1,2,3,4tetrahydro-SH- 1 benzopyrano [3 ,4-c] pyridine, dissolved in 150 ml. ofabsolute ethanol and 30 ml. of glacial acetic acid, was reduced withhydrogen at 45.5 pounds p.s.i. over 0.7 g. of a 10%palladium-on-charcoal catalyst. When reduction was complete, thesolution was filtered from the catalyst, the filtrate evaporated todryness, and the residue taken into chloroform and washed with aqueouspotassium bicarbonate. The organic layer was then washed with water,dried over sodium sulfate, evaporated to dryness, and the red solidresidue recrystallized once from acetonitrile and once from benzene togive 2.6 g. of 5,5 dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-1,2, 3,4tetrahydro 5H [1]benzopyrano[3,4-c]pyri-dine, M.P. 168170 C.

Analysis.Calcd. for C H NO (percent): C, 77.26; H, 9.87; N, 3.92. Found(percent): C, 77.32; H, 10.06; N, 4.14.

(D) 5,5 dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-3- (2 propynyl) 1,2,3,4tetrahydro-5H-[1]benzopyrano- [3,4-c1pyridine hydrochloride.A mixture of1.6 g. (0.004 mole) of 5,5-dimethyl-10-hydroxy-8-(3-methyl-2- octyl)1,2,3,4 tetrahydro 5H [1]benzopyrano[3,4- c]pyridine, 0.52 g. (0.004mole) of 3-bromo-1-propyne, 0.6 g. (0.006 mole) of anhydrous sodiumcarbonate, 0.1 g. of sodium iodide, and 30 ml. of absolute ethanol wasstirred and refluxed under nitrogen for sixteen hours, cooled, filtered,and the filtrate evaporated to dryness. The red gummy residue Wasextracted with petroleum ether (B.P. 3060 C.), the extracts concentratedto a small volume, filtered to remove about 300 mg. of a pink solid, andthe filtrate evaporated to dryness. The resulting residue was taken intoether, the solution saturated with anhydrous hydrogen chloride, dilutedwith petroleum ether, and cooled to give 372 mg. of 5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl) 3 (2 propynyl)-1,2,3, 4-tetrahydro 5H[1]benzopyrano[3,4-c]pyridine hydrochloride, M.P. -125 C.

Analysis.Calcd. for C H NO .HCl (percent): C, 72.28; H, 8.86; N, 3.24.Found (percent): C, 71.91; H, 8.43; N, 3.19.

EXAMPLE 3 3-allyl-5,5-dimethyl 10 hydroxy-8-(3-methyl-2-octyl)- 1,2,3,4tetrahydro 5H [1]benzopyrano[3,4-c]pyridine hydrochloride A mixture of1.6 g. (0.004 mole) of 5,5-dimethyl-10- hydroxy 8 (3-methyl 2octyl)-l,2,3,4-tetra.hydro- 5H [1]benzopyrano[3,4 c]pyridine, 0.51 g.(0.004 mole) of 3-bromo-1-propene, 0.6 g. (0.006 mole) of anhydrussodium carbonate, and 30 m1. of absolute ethanol Was stirred andrefluxed under nitrogen for sixteen hours, cooled, filtered, and thefiltrate evaporated to dryness. The residue was taken into petroleumether (B.P. 30-60 C.), filtered, and the filtrate saturated withanhydrous hydrogen chloride to give a yellow gummy precipitate, whichwas recrystallized from a petroleum ether-ethyl acetate mixture giving0.54 g. of 3-allyl- 5,5-dimethyl 10 hydroxy 8 (3-methyl 2 octyl)-1,2,3,4-tetrahydro 5H [l]benzopyran0[3,4-c]pyridine hydrochloride, M.P.208210 C.

Analysis.Calcd. for C H NO .HCl (percent): C, 71.94; H, 9.29; N, 3.22.Found (percent): C, 72.08; H, 9.31; N, 3.04.

EXAMPLE 4 3 (trans 3 chloroallyl) 5,5-dimethyl-10-hydroxy- 8 (3methyl-2-octyl) 1,2,3,4-tetrahydro 5H [1] benzopyrano[3,4-c]pyridinehydrochloride was prepared from 1.6 g. (0.004 mole) of5,5-dimethyl-10-hydroxy-8- (3-methyl-2-octyl) 1,2,3,4 tetrahydro 5H[1]benzopyrano[3,4-c]pyridine, 0.48 g. (0.004 mole) of trans-1,3-dichloro-1-propene, 0.6 g. (0.006 mole) of anhydrous sodiumcarbonate, and 30 ml. of absolute ethanol using the manipulativeprocedure described above in Example 3. The crude product was isolatedin the form of its hydrochloride salt, and the latter recrystallizedonce from a petroleum ether/ethyl acetate mixture, and once from anethyl acetate/ethanol mixture giving 0.31 g. of 3- (trans 3 chloroallyl)5,5 dimethyl-10-hydroxy-8- (3 methyl 2octyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridinehydrochloride, M.P. 250253 C.

Analysis.Calcd. for C H ClNO .HCl (percent): C, 66.66; H, 8.39; N, 2.99.Found (percent): C, 66.41; H, 8.52; N, 2.88.

EXAMPLE 5 10-hydroxy-3-(2-propynyl) -5,5,8-trimethyl-1,2,3,4-tetrahydro-SH- 1]benzopyrano [3 ,4-c]pyridine (A) 3-benzyl 10hydroxy-8-methyl-5-oxo-1,2,3,4- tetrahydro 5H [1]benzopyrano[3,4c]pyridine.1 benzyl-3-carbethoxy-4-piperidone hydrochloride, (104 g.,0.33 mole) was mixed with 50 g? (0.4 mole) of 5 -methylresorcinol, andthe mixture treated dropwise over a period of one hour with ml. ofconcentrated sulfuric acid. Phosphorus oxychloride (60 ml.) was thenadded all at once, and the mixture stirred at room temperature forsixteen hours. Isolation of the product according to the proceduredescribed above in Example 1-A afforded 0.6 g. of3-benzyl-10-hydroxy-8methyl-5-oxo-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridine,M.P. 222- 224 C.

Analysis.Calcd. for C H NO (percent): C, 74.74; H, 5.96; N, 4.36. Found(percent): C, 74.58; H, 5.86; N, 4.29.

(B) 10 hydroxy 8 methyl-S-oxo-l,2,3,4-tetrahydro-H-[1]benzopyrano[3,4-c]py1idine was prepared by catalytic debenzylationof 2 g. (0.006 mole) of 3-benzyl- IO-hydroxy 8 methyl 5oxo-1,2,3,4-tetrahydro-5H- [1]benzopyrano[3,4-c] pyridine in 100 ml. ofglacial acetic acid and 50 ml. of absolute ethanol under 54 poundsp.s.i. of hydrogen over 0.5 g. of palladiumon-charcoal using themanipulative procedure described above in Example 2-C. Recrystallizationof the crude product from ethanol afforded 0.1 g. of 10-hydroxy-8-methyl-S-oxo-1,2,3,4-tetrahydro 5H [1]benzopyrano [3,4-c]pyridine, M.P.250253 C.

Analysis.Calcd. for C H NO (percent): C, 67.52; H, 5.67; N, 6.06. Found(percent): C, 67.24; H, 5.71; N, 6.04.

(C) 10 hydroxy 8 methyl-5-oxo-3-(2-propynyl)- 1,2,3,4 tetrahydro 5H[1]benzopyrano[3,4-c]pyridine was prepared from 2.9 g. (0.01 mole) oflO-hydroxy 8 methyl 5 0x0-1,2,3,4-tetrahydro-5H-[l]benzopyrano[3,4-c]pyridine, 2.1 g. (0.02 mole) of anhydrous sodiumcarbonate, and 1.19 g. (0.01 mole) of 3-bromo-1-propyne in 175 ml. ofabsolute ethanol using the manipulative procedure described above inExample 3. The crude product was recrystallized from acetonitrile togive 0.14 g. of 10-hydroxy-8-methyl-5-oxo-3-(2-propynyl)-1,2,3,4tetrahydro 5H [1]benzopyrano[3,4- c]pyridine, M.P. 197-200 C.

Analysis.-Calcd. for C H NO (percent): C, 71.36; H, 5.61; N, 5.20. Found(percent): C, 71.14; H, 5.93; N, 5.14.

(D) 10 hydroxy 3 (2 propynyl)-5,5,8-trimethyl- 1,2,3,4-tetrahydro 5H[1]benzopyrano[3,4-c]pyridine is prepared by reacting 10 hydroxy 8methyl -5- oxo 3 (2-propynyl)-1,2,3,4-tetrahydro 5H[1]benzopyrano[3,4-c]pyridine with methyl magnesium iodide in anisoleaccording to the manipulative procedure described above in Example 1-B.

EXAMPLE 6 3-benzyl-10-hydroxy 5,5,8 trimethyl-l,2,3,4 tetrahydro 5H[1]-benzopyrano[3,4-c]pyridine was prepared from 15.6 g. (0.048 mole) of3-benzyl-10-hydroxy- 8 methyl 5-oxo-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridine and 0.5 mole of methyl magnesium bromide in 350 m1. ofanisole, and 120 ml. of pyridine using the manipulative proceduredescribed above in Example l-B. The crude product was recrystallizedfrom acetonitrile to give 4.0 g. of 3-benzyl-10-hydroxy-5,5,8-trimethyl-1,2,3,4-tetrahydro 5H [1]benzopyrano[3,4- c]pyridine, M.P.206-208 C.

Analysis.-Calcd. for C H NO (percent): C, 78.77; H, 7.51; N, 4.18. Found(percent): C, 79.15; H, 7.36; N, 4.28.

EXAMPLE 7 5,5 dimethyl 10 hydroxy-8-(3-methyl-2-octyl)-3-(2- propynyl)1,2,3,4 tetrahydro 5H [1]benzopyrano [3,4-c]pyridine hydrochloride (A)10 hydroxy 8 (3 methyl-2-octyl)-5-oxo- 1,2,3,4 tetrahydro 5H[1]benzopyrano[3,4-c]pyridine was prepared by catalytic debenzylation of3-benzyl-l0- hydroxy 8 (3methyl-2-octyl)-5-oxo-1,2,3,4-tetrahydro-SH-[1]benzopyrano[3,4-c]pyridinein 200 ml. of absolute ethanol and ml. of glacial acetic acid under 50pounds p.s.i. of hydrogen over 1 g. of a 10% palladium-on-charcoalcatalyst using the manipulative procedure described above in Example2-C. The crude product was recrystallized twice from acetonitrile giving1.9 g. of 10-hydroxy 8 (3 methyl-Z-octyl)-5-0xo-1,2,3,4- tetrahydro 5H[1]benzopyrano[3,4-c]pyridine, M.P. 177-179 C.

Analysis.Calcd. for C H NO (percent): C, 73.43; H, 8.51; N, 4.08. Found(percent): C, 73.06; H, 8.47; N, 4.23.

10-hydroxy 8 (3 methyl-Z-octyl)-5-oxo-1,2,3,4tetrahydro-5H-[1]benzopyrano[3,4-c]pyridine was also prepared byreaction of 5.8 g. (0.025 mole) of 3-carbethoxy-4-piperidonehydrochloride with 5.9 g. (0.025 mole) of5-(3-methyl-2-octyl)-resorcinol in 11.5 ml. of concentrated sulfuricacid and 4.5 ml. of phosphorus oxychloride using the manipulativeprocedure described above in Example 1-A. Recrystallization of the crudeproduct from acetonitrile afforded 0.75 g. of 10-hydroxy- 8-(3 methyl 2octyl) 5 oxo-1,2,3,4-tetrahydro- 5H-[1]benzopyrano[3,4-c]pyridine, M.P.17918l C.

(B) 10-hydroxy-8-(3-methyl 2 octyl) 5 oxo-3- (2-propynyl)1,2,3,4-tetrahydro 5H [1]benzopyrano [3,4c]pyridine hydrochloride wasprepared by reacting of 3.4 g. (0.01 mole) of10-hydroxy-8-(3-methyl-2-octyl)- 5-oxo-l,2,3,4 tetrahydro 5H[1]benzopyrano[3,4-c] pyridine with 1.18 g. (0.01 mole) of3-bromo-1-propyne in ml. of absolute ethanol in the presence of 2.1 g.(0.02 mole) of anhydrous sodium carbonate using the manipulativeprocedure described above in Example 3. The crude product was isolatedin the form of its hydrochloride salt and the latter recrystallized fromethyl acetate giving 0.67 g. of 10 hydroxy-8-(3-methyl-2 octyl) 5 0X0 3(2-propyny1)-1,2,3,4-tetrahydro- 5H-[1]benzopyrano[3,4-c1pyridinehydrochloride, M.P. 132-135 C.

Analysis.-Calcd for C H NO -HCl (percent): C, 68.97; H, 7.71; N, 3.35.Found (percent): C, 68.86; H, 7.79; N, 3.37.

C) 5,5-dimethyl 10 hydroxy 8 (3-methyl 2 octyl) 3 (2 propynyl)1,2,3,4-tetrahydro-5H-[l] benzopyrano[3,4-c]pyridine hydrochloride canbe prepared by reaction of 10-hydroxy-8-(3-methyl-2-octyl)- 5-oxo 3 (2propynyl) 1,2,3,4-tetrahydro-5H-[l] benzopyrano[3,4-c]pyridinehydrochloride with methyl magnesium iodide in anisole, using themanipulative procedure described above in Example 1-B.

EXAMPLE 8 5,5-di (1 hexyl) 10-hydr0xy-3-methyl-8-(3-methyl- 2-octyl)1,2,3,4 tetrahydro 5H [1]benzopyrano [3,4-c] pyridine Following aprocedure similar to that described in EX- ample 1-B hereinabove,IO-hydroxy 3 methyl-8-(3- methyl-Z-octyl) 1,2,3,4 tetrahydro 5H[1]benzopyrano[3,4-c1pyridine is reacted with n-hexyl magnesium bromidein anisole to give 5,5-di-(1-hexyl)-10-hydroxy- 3-methyl 8 (3 methyl 2octyl)-1,2,3,4-tetrahydro- 5H-[ 1 benzopyrano 3,4-c] pyridine.

EXAMPLE 9 3-cinnamyl 5,5 dimethyl 10 hydroxy-8-(3-methyl- 2 octyl)1,2,3,4 tetrahydro- 5H [1]benzopyrano [3,4-c]pyridine Following aprocedure similar to that described in Example 3,5,5-dimethyl-IO-hydroxy-S-(3 methyl 2 0ctyl)-1,2,3,4 tetrahydro 5H[1]benzopyrano[3,4-c] pyridine is reacted with cinnamyl chloride in thepresence of anhydrous sodium carbonate to give 3-cinnamyl- 5,5-dimethyl10 hydroxy-8-(3-methyl-2-octyl)1,2,3,4- tetrahydro-SH- l benzopyrano[3,4-c] pyridine.

EXAMPLE l0 3 acetyl 5,5 dimethyl 10 hydroxy-8-(3-methyl-2 octyl)1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c] pyridine By reaction of5,5-dimethyl-1 0-hydroxy-8-(3 methyl- 2-octyl)-1,2,3-4-tetrahydro 5H[1]benzopyrano[3,4-c]

pyridine with an equimolar amount of acetyl chloride in, for example abenzene solution, in the presence of triethylamine, there can beobtained 3-acetyl-5,5-dimethyl- 1 1 IO-hydroxy 8 (3methyl-Z-octyl)-1,2,3,4-tetrahydro- 5H- 1 1 benzopyrano[ 3,4-c]pyridine.

EXAMPLE ll 5,5-dimethyl 10 hydroxy 8 (3-methyl-2-octyl)-3- phenylacetyl1,2,3,4 tetrahydro 5H[1]benzopyrano [3 ,4-c] pyridine By reaction of5,5-dimethyl-l-hydroxy 8 (3-methyl- 2-octyl)-1,2,3,4-tetrahydro H[l]benzopyrano[3,4-c] pyridine with phenylacetyl chloride in thepresence of pyridine in a benzene solution, there can be obtained5,5-dimethyl-l0-hydroxy 8 (3 methyl 2 octyl)-3- phenylacetyl 1,2,3,4tetrahydro 5H [1]benzopyrano [3,4-c1pyridine.

EXAMPLE 12 5,5 dimethyl 1O hydroxy 8 (3-methyl-2octyl)-3- (2phenylethyl) 1,2,3,4 tetrahydro 5H-[1]benzopyrano[3,4-c-]-Pyridine Byreduction of 5,5-dimethyl-IO-hydroxy-S-(S-methyl- 2 octyl 3phenylacetyl-1,2,3,4-tetrahydro-5H-[1]benzopyrano-[3,4,-c]pyridine Withlithium aluminum hydride in tetrahydrofuran solution, there can beobtained 5,5- dimethyl 1O hydroxy 8 (3 methyl-2-octyl)-3-(2-phenylethyl) 1,2,3,4 tetrahydro 5H-[11benzopyrano- [3,4-c]pyridine.

EXAMPLE 13 5,5 dimethyl l0 hydroxy 8 (3 methyl-2-octy1)-3- [2 (4methylphenyl)ethyl] 1,2,3,4 tetrahydro-5H- [11benzopyrano-[3 ,4-c]pyridine Following a procedure similar to that described in EX- ample 3hereinabove, 5,5 dimethyl 1O hydroxy 8 (3 methyl 2 octyl) 1,2,3,4tetrahydro 5H [1] benzopyrano [3,4 c]pyridine is reacted with 2 (4methylphenyl)ethyl bromide in absolute ethanol in the presence ofanhydrous sodium carbonate to give 5,5 dimethyl 10 hydroxy 8- (3 methyl2 octyl) 3 [2 (4 methylphenyl)ethyl] 1,2,3,4 tetrahydro 5H[11benzopyrano [3,4 0] pyridine.

EXAMPLE 14 5,5 dimethyl 10 hydroxy 8 (3 methyl 2 octyl)- 3 [3 (3,4dimethoxyphenyl) propyl] 1,2,3,4 tetrahydro 5H [1] benzopyrano[3,4c]pyr1d1ne Following a procedure similar to that described in EX- ample3 hereinabove, 5,5 dimethyl 10 hydroxy-8(3- methyl 2 octyl) l,2,3,4tetrahydro 5H [1]benzopyrano[3,4-c]pyridine is reacted with 3 (3,4dimethoXyphenyDpropyl bromide in absolute ethanol, in the presence ofanhydrous sodium carbonate to give 5,5 dimethyl 10 hydroxy 8 (3 methyl 2octyl) 3 [3 (3,4 dimethoxyphenyl)propyl] 1,2,3,4 tetrahydro-5H-[1]benzopyrano 3,4-c] pyridine.

EXAMPLE 15 5,5 dimethyl 10 hydroxy 8 (3 methyl 2 octyl)- 3 [1 (2,4,6tribromophenyl) ethyl] 1,2,3,4- tetrahydro 5H [1]benzopyrano[3,4-c1pyridine Following a procedure similar to thatdescribed in Example 3 hereinabove, 5,5 dimethyl l0 hydroxy 8 (3 methyl2 octyl) l,2,3,4 tetrahydro 5H [1] benzopyrano[3,4-c]pyridine is reactedwith 1 (2,4,6 tribromophenyl)ethyl bromide in the presence of anhydroussodium carbonate to give 5,5 dimethyl 10 hydroxy 8 (3 methyl 2 octyl) 3[1 -'(2,4,6 tribromophenyl) ethyl] 1,2,3,4 tetrahydro 5H [l]benzopyrano[3,4-c]pyridine.

12 EXAMPLE 16 5,5 dimethyl 1O hydroxy 8 (3 methyl 2 octyl)- 3 [4 (4nitrophenyl)butyl] 1,2,3,4 tetrahydro 5H [1]benzopyrano [3,4-c]pyridineFollowing a procedure similar to that described in EX- ample 3hereinabove, 5,5 dimethyl 10 hydroxy 8 (3 methyl 2 octyl) l,2,3,4tetrahydro 5H [l] benzopyrano [3,4-c1pyridine is reacted with 4 (4nitrophenyl)butyl bromide in the presence of anhydrous sodium carbonateto give 5,5 dimethyl 1O hydroxy 8 (3 methyl 2 octyl) 3 [4 (4nitrophenyl)butyl]- l,2,3,4 tetratydro 5H [1]benzopyrano[3,4-c]pyridine.

EXAMPLE 17 5,5 dimethyl 10 hydroxy 8 (3 methyl 2 octyl) 3 [2 (4methylmercapto phenyl)ethyl] 1,2,3,4- tetrahydro 5H[1]benzopyrano[3,4-c1pyridine EXAMPLE 18 5,5 dimethyl 10 hydroxy 8 (3methyl 2 octyl)- 3 {3 [l (3,4 methylenedioxy phenyl) 1 butenyl]} 1,2,3,4tetrahydro 5H [1]benzopyrano- [3,4-c] pyridine Following a proceduresimilar to that described in EX- ample 3 hereinabove, 5,5 dimethyl 10hydroxy 8 (3 methyl 2 octyl) 1,2,3,4 tetrahydro 5H [1]benzopyrano[3,4-c]pyridine is reacted with 3 [1 (3,4-methylenedioxyphenyl) 1 butenyl]bromide in the presence of anhydroussodium carbonate to give 5,5 dimethyl 1O hydroxy 8 (3 methyl 2 octyl) 3{3 [1 (3,4 methylenedioxyphenyl) 1 butenyl]} 1,2,3,4 tetrahydro 5H[1]benzopyrano[3,4-c]pyridine.

EXAMPLE 19 5,5 dimethyl 10 hydroxy 8 (3 methyl 2 octyl)- 3 {3 [1(4acetylaminophenyl) 1 butenyl]} 1,2,3,4 tetrahydro 5H [1]benzopyrano[3,4-c] pyridine Following a procedure similar to thatdescribed in Example 3 hereinabove, 5,5 dimethyl 10 hydroxy 8 (3 methyl2 octyl) 1,2,3,4-tetrahydro 5H [1] benzopyrano[3,4-c]pyridine is reactedWith 3 [1 (4 acetylaminophenyl) butenyl] bromide in the presence ofanhydrous sodium carbonate to give 5,5 dimethyl 10 hydroxy 8 (3 methyl 2octyl) 3 {3 [1 (4 acetylaminophenyl) 1 butenyl]} 1,2,3,4 tetrahydro 5H[1]benzopyrano [3,4-c]pyridine.

EXAMPLE 20 5,5 dimethyl 10 hydroxy 8 (3 methyl 2 octyl)-3-{4-[1-(3-trifluoromethyl 'phenyl) 1 'butenyl]}-1,2, 3,4-tetrahydro-5H- 1 ]:benzopyrano [3,4-c] pyridine Following a proceduresimilar to that described in Example 3 hereinabove, 5,5 dimethyl 10hydroxy 8- (3 methyl 2 octyl) 1,2,3,4 tetrahydro 5H [l]benzopyrano[3,4-c]pyridine is reacted with 4 [1 (3trifiuoromethylphenyl) 1 butenyl]bromide in the presence of anhydroussodium carbonate to give 5,5 dimethyle l0 hydroxy 8 (3 methyl 2 octyl) 3{4 [1 (3 trifluoromethylphenyl) 1 butenyl]} 1,2,3,4 tetrahydro 5H[1]benzopyrano[3,4-c] pyridine.

13 EXAMPLE 21 3 cyclopropylcarbonyl 5,5 dimethyl 10 hydroxy v 8 (3methyl 2 octyl) 1,2,3,4 tetrahydro 5H [1]benzopyrano[3,4-c] pyridineFollowing a procedure similar to that described in Example 11hereinabove, 5,5 dimethyl 10 hydroxy 8 (3 methyl 2 octyl) l,2,3,4tetrahydro 5H [1] benzopyrano[3,4-c]pyridine is reacted withcyclopropylcarbonyl chloride in benzene solution in the presence ofpyridine to give 3 cyclopropyl carbonyl 5,5dimethyl-10-hydroxy8-(3-methyl 2 octyl)-1,2,3,4-tetrahydro-SH- 1benzopy-rano 3,4-c] pyridine.

EXAMPLE 22 3 -cyclopropylmethyl-5 ,5 -dimethyl- 1 O-hydroxy-S- 3methyl-Z-octyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano 3,4-c] pyridineFollowing a procedure similar to that described in Example 12hereinabove, 3-cyclopropylcarbonyl-5,5 dimethyl-10-hydroxy-8-(3 methyl 2octy1)-1,2,3,4-tetrahydro 5H [1] benzopyrano[3,4-c]pyridine is reducedwith lithium aluminum hydride in tetrahydrofuran to give3-cyclopropylmethyl-5,S-dimethyl-10-hydroxy 8-(3-methyl-2-octyl)-1,2,3,4 tetrahydro 5H-[1]benzopyrano [3,4-c] pyridine.

EXAMPLE 23 5 ,5 -dimethyl-10-hydroxy-8- 3 -methyl-24)ctyl -3- 3-phenyl-Z-propynyl) 1,2,3,4,tetrahydro-5H-[1]benzopyrano 3 ,4-c] pyridineFollowing a procedure similar to that described in Example 3hereinabove, 5,5 -dimethyl-l-hydroxy-8-(3 methyl-2-octyl)-l,2,3,4tetrahydro H-[1]benzopyrano [3,4-c]pyridine is reacted with3-phenyl-2-propynyl bromide in absolute ethanol in the presence ofanhydrous sodium carbonate to give 5,5-dimethyl-l0-hydroxy-8-(3-methyl-Z-octyl)-3-(3-phenyl-2-propynyl) 1,2,3,4 tetra hydro-5H-[ 1benzopyrano 3,4-c] pyridine.

EXAMPLE 24 acetoxy-S- 3-methyl-2-octyl -3 ,5 ,5 -trimethyl-1 ,2,3 ,4-tetrahydro-5H-[ l -benzopyrano [3,4-c] pyridine By reactinglO-hydroxy-8-(3-methyl-2-octyl)-3,5,5-trimethyl-1,2,3,4 tetrahydro 5H[l]benzopyrano[3,4-c] pyridine with acetic anhydride, there is obtained10- acetoxy 8 (3 methyl 2 octyl) 3,5,5 trimethyl-1,2,3,4-tetrahydro-5H-[ 1 benzopyrano [3 ,4-c] pyridine.

EXAMPLE 25 10-methoxy-8- (3 -methyl-2-octyl) 3 ,5 ,5 -trimethyl 1,2,3,4- tetrahydro-5H-[ 1 benzopyrano 3,4-c] pyridine By reactinglO-hydroxy-8-(3-rnethyl-2-octyl)-3,5,5-trimethyl-1,2,3,4 tetrahydro 5H[1]benzopyrano[3,4-c] pyridine with methyl iodide in the presence ofsodium ethoxide, there is obtained 10-methoxy-8- (3-methyl-2- octyl)3,5,5 trimethyl 1,2,3,4 tetrahydro 5H [1] benzopyrano[ 3,4-c] pyridine.

EXAMPLE 26 IO-carbamyloxy-S- (3-methyl-2-octyl) -3,5,5-trimethyl-1,2,3,4-tetrahydro-5H-[ 1 benzopyrano [3,4-c] pyridine By reacting10-hydroxy-8-(3-methyl-2-octyl)-3,5,5-trimethyl-1,2,3,4 tetrahydro 5H[1]benzopyrano[3,4-c] pyridine with an equimolar amount of phosgene inthe presence of dimethylaniline, and reacting the resultingchloroformate with liquid ammonia, there is obtained 10-carbamyloxy-8-(3 methyl 2 octyl) 3,5,5 trimethyll,2,3 ,4-tetrahydro-5H-1 ]benzopyrano [3 ,4-c] pyridine.

14 EXAMPLE 27 10-( N-methylcarbamyloxy)-8-(3-methyl-2-0ctyl) 3,5 ,5-trimethyl-1 ,2,3 ,4-tetrahydro-5H-[1]benzopyrano [3,4-c] pyridine Byreacting 10-hydr0xy-8-(3-methyL2-octyl)-3,5,5-trimethyl-1,2,3,4tetrahydro 5H [1]benzopyrano[3,4-c] pyridine with an equimolar amount ofphosgene in the presence of dimethylaniline, and reacting the resultingchloroforrnate with methylamine, there is obtained 10- (Nmethylcarbamyloxy) 8 (3 methyl 2 octyl)- 3,5,5 trimethyl 1,2,3,4tetrahydro 5H [11benzopyrano [3 ,4-c] pyridine.

EXAMPLE 28 10- N,N-dimethylcarbamyloxy) -8- 3-methyl-2-octyl) 3,5 ,5-trimethyl- 1 ,2,3 ,4-tetrahydro-5H-[1]benzopyrano 3,4-c] pyridine Byreacting 10-hydroxy-8-(3-rnethyl-2-octyl)-3,5,5-trimethyl-1,2,3,4tetrahydro 5H [1]benzopyrano[3,4-c] pyridine .with an equimolar amountof phosgene in the presence of dimethylaniline, and reacting theresulting chloroformate with dimethylamine, there is obtained 10'- (N,Ndimethylcanbamyloxy) 8 (3-methyl 2 octyl)- 3,5,5 trimethyl 1,2,3,4tetrahydro-5H[l]benzopyrano- [3,4-c]pyridine.

EXAMPLE 29 8- 3 -methyl-2-octyl)-10-phosphonyloxy-3 ,5 ,5 -trirnethyl-1,2,3 ,4-tetrahydro-5H-[1]benzopyrano[3 ,4-c] pyridine By reacting10-hydroxy-8-(3methyl-2-octyl)-3,5,5-tri methyl-1,2,3,4 tetrahydro 5H[l]benzopyrano[3,4c] pyridine with one molar equivalent amount ofphosphorus oxychloride in toluene in the presence of pyridine, andreacting the resulting dichlorophosphinate with aqueous potassiumcarbonate, there is obtained 8-(3-rnethyl-2- octyl) 1O phosphonyloxy3,5,5 trimethyl 1,2,3,4- tetrahydro-SH- l benzopyrano [3,4-c] pyridine.

EXAMPLE 30 10-hy droxy-8 3 -methyl-2-octyl -3 ,5, 5 -trimethyl-5 H-[1]benzopyrano[ 3 ,4-c] piperidine By reducing10-hydroxy-8-(3-methyl-2-octyl)-3,5,5-trimethy1-1,2,3,4 tetrahydro 5H[l]benzopyrano[3,4-c] pyridine with hydrogen in an ethanol solvent overa Raney nickel catalyst, there is obtained 10-hydroxy-8-(3-methyl-2-octyl)-3,5,5 trimethyl 5H [1]benzopyrano [3,4-c]piperidine.

EXAMPLE 31 By reducing the compounds of Examples 2-B, 2-C, 8, 10, ll,12, 13, 14, 15, 17, 21, 22, 24, 25, 26, 27, 28, and 29 with hydrogenover a Raney nickel catalyst following the procedure described above inExample 30, there can be obtained the following respective compounds ofFormula Ila:

(A) 3 benzyl 5,5 dimethyl l0 hydroxy 8 (3- methyl-Z-octyl) -5H- lbenzopyrano[ 3,4-c] piperidine.

(B) 5,5 dimethyl 10 hydroxy 8 (3 methyl 2- octyl)-5H-[1]benzopyrano[3,4-c] piperidine.

(C) 5,5 di (1 hexyl) l0 hydroxy 3 methyl- 8-(3-methyl 2octyl)-5H-[1]benzopyrano[3,4-c]piperidine.

(D) 3 acetyl 5,5-dimethyl-10-hydroxy-8-(3-methyl- 2-octy1) -5H[1]benzopyrano[3,4-c]piperidine.

(E) 5,5 dimethyl 10-hydroxy-8-(3-methyl-2-octyl)- 3-phenylacetyl-5H- 1benzopyrano 3,4-c] piperidine.

(F) 5,5 dimethyl 10-hydroxy-8-(3-methyl-2-octyl)- 3- (2-phenylethyl)-5H-[ 1]benzopyrano[3,4-c]piperidine.

(G) 5,5 dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-3- [2 (4methylphenyl)ethyl]-5H-[l]benzopyrano[3,4-c] piperidine.

(H) 5,5 dimethyl l-hydroxy-8-(3-methyl-2-octyl)- 3 [3 (3,4dimethoxyphenyl)propyl]-H-[1]benzopyrano [3,4-c] piperidine.

(J) 5,5 dimethyl -hydroxy-8-(3-methyl-2-octyl)-3- [1 (2,4,6tri'bromophenyl)ethyl]-5H-[11benzopyrano [3,4c]piperidine.

(K) 5,5 dimethyl 10-hydroxy-8-(3-methyl-2-octyl)- 3 [2 (4methylmercaptophenyl)ethyl]-5H-[l]benzopyrano[3,4-c]piperidine.

(L) 3 cyclopropylcarbonyl 5,5-dimethyl-10-hydroxy- 8 (3methyl-2-octyl)-5H-[1]benzopyrano[3,4-c1piperidine.

(M) 3 cyclopropylmethyl 5,5-dimethyl-10-hydroxy- 8 (3methyl-Z-octyl)-5H-[l]benzopyrano[3,4-c]piperidine.

(N) 10 acetoxy-8-(3-methyl-2-octyl)-3,5,5-trimethyl-5H-[1]benzopyrano[3,4-c]piperidine.

(O) 10 methoxy 8 (3 methyl 2-octyl)-3,5,5,-trimethy-SH-1]benzopyrano[3,4-c]piperidine.

(P) 10 carbamyloxy8-(3-methyl-2-octyl)-3,5,5-trimethyl-5H-[1]benzopyrano[3,4-c]piperidine.

(Q) 10 (N methylcarbarnyloxy) 8 (3-methyl-2- octyl) 3,5,5trimethyl-5H-[1]benzopyrano[3,4-c]piperidine.

(R) 10 (N,N dimethylcarbamyloxy)-8-(3-methyl-2- octyl) 3,5,5trimethy1-5H-[1]benzopyrano[3,4-c]piperidine.

(S) 8 (3- methyl-Z-octyl)-10*-phosphonyloxy-3,5,5- trimethyl-SH-1]benzopyrano [3,4-c] piperidine.

EXAMPLE 32 3 allyl 5,5 dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-5H-[l1benzopyrano[3,4-c1piperidine EXAMPLE 33 3 (trans 3-chloroally1) -5,5 -dimethyll 0-hydroxy-8- (3- methyl-2-octyl) -5H- 1 benzopyrano[3,4-c1p1perid1ne Following a procedure similar to that described inEx-' ample 3 hereinabove, 5,5 dimethyl 10 hydroxy-8-(3- methyl 2octyl)-5H-[1]benzopyrano[3,4-c]piperidine is reacted withtrans-1,3-dich1oro-1-propene in absolute ethanol in the presence ofanhydrous sodium carbonate to give 3 (trans 3chloroallyl)-5,5-dimethyl-10-hydroxy-8-(3- methyl-2-octyl) -5 H- 1benzopyrano[3,4-c] piperidine.

EXAMPLE 34 10 hydroxy 3- (2-propynyl) -5,5,8-trimethyl-5H- 1]benzopyrano [3,4-c] piperidine Following a procedure similar to thatdescribed in Example 3 hereinabove, 10 hydroxy 5,5,8-trimethyl-5H-[1]benzopyrano[3,4-c]pyridine is reacted with 3-bromo-lpropyne inabsolute ethanol in the presence of anhydrous sodium carbonate to give10 hydroxy 3 (2-propyny1)-5,5,8-trimethyl-5H-[1]benzopyrano[3,4-c1piperidine.

EXAMPLE 35 5,5 dimethyl 10 hydroxy-S-(3-methyl-2-octyl)-3-(2- pro pynyl)-5H- 1]benzopyrano[ 3,4-c] piperidine Following a procedure similar tothat described in Example 3 hereinabove, 5,5 dimethyl 10 hydroxy-8-(3-methyl 2-octyl)-5H-[1]benzopyrano[3,4-c]piperidine is reacted with3-bromo-1-propyne in absolute ethanol in the presence of anhydroussodium carbonate to give 5,5-dimethyl 1O hydroxy 8(3-methy1-2-octyl)-3-(2-propynyl)-5H-[1]benzopyrano[3,4-c1piperidine.

1 6 EXAMPLE 36 3 cinnamyl 5,5 dimethyl-10-hydroxy-8-(3-methyl-2- octyl)-5H-[ 11benzopyrano [3,4-c1piperidine Following a procedure similar tothat described in Example 3 hereinabove, 5,5 dimethyl 10 hydr0Xy-8-(3methyl 2-octyl)-5H-[1]benzopyrano[3,4-c]piperidine is reacted withcinnamyl chloride in absolute ethanol in the presence of anhydroussodium carbonate to give 3-cinnamyl 5,5 dimethyl10-hydroxy-8-(3-methyl-2-octyl)- 5H-[1]benzopyrano[3,4-c] piperidine.

EXAMPLE 37 5 ,5 dimethyl IO-hydroxy-S- 3-methy1-2-octyl) -3- [4- (4-nitrophenyl) butyl] -5H-[ 1]benzopyrano[3,4-c]piperidine Following aprocedure similar to that described in Example 3 hereinabove, 5,5dimethyl 1O hydroxy-8-(3- methyl2-octyl)-5H-[1]benzopyrano[3,4-c]piperidine is reacted with4-(4-nitrophenyl)butyl bromide in absolute ethanol in the presence ofanhydrous sodium carbonate to give 5,5 dimethyl 1Ohydroxy-8-(3-methyl-2-octyl)-3- [4 (4nitrophenyl)butyl]-5H-[1]benzopyrano[3,4-c] piperidine.

EXAMPLE 38 5,5-dimethyl-lO-hydroxy-8-(3-methyl 2 octyl)-3-{3-[1- (3,4methylenedioxyphenyl) 1 butenyl]}-5H-[l] benzopyrano 3,4-c] piperidineFollowing a procedure similar to that described in Example 3hereinabove, 5,5 dimethyl-l0-hydroxy-8-(3- methyl-2-octyl)-5H[l]benzopyrano[3,4-c]piperidine is reacted with3-[1-(3,4-methylenedioxyphenyl)-l-butenyl] bromide in absolute ethanolin the presence of anhydrous sodium carbonate to give5,5-dimethyl-10-hydroxy-S-(3-methyl-2-octyl)-3-{3-[l-(3,4-methylenedioxyphenyl) 1 butenyl] }-5H- 1benzopyrano [3 ,4-c] -piperidine.

EXAMPLE 39' 5,5-dimethyl-10-hydroxy-8-(3 methyl 2-octyl)-3-{3-[l- (4acetylaminophenyl) 1 butenyl]}-5H-[l]benzopyrano [3,4-c] -piperdineFollowing a procedure similar to that described in Example 3hereinabove, 5,5-dimethyl-10-hydroxy-8-(3- methyl-Z-octyl)5H-[1]benzopyrano[3,4-c1piperidine is reacted with3-[1-(4-acetylaminophenyl) l-butenyl] bromide in absolute ethanol in thepresence of anhydrous sodium carbonate to give5,5-dimethyl-IO-hydroxy-S-(3- methyl-2-octyl)-3-{3-[1 (4acetylaminophenyl) 1 butenyl] }-5H- 1 benzopyrano [3 ,4-c] -piperidine.

EXAMPLE 40 5,5-dimethy1-10-hydroxy-S-(3-methyl 2 octyl)-3-{4-[1-(3-trifluoromethylphenyl) 1 butenyl]}-5H-[1]benzopyrano[3,4-c1piperidine Following a procedure similar to that described inExample 3 hereinabove, 5,5-dimethyl-10-hydroxy-S-(3- methyl-Z-octyl)5H-[1]benzopyrano[3,4-c]piperidine is reacted with4-[1-(3-trifluoromethylphenyl)-1 butenyl] bromide in absolute ethanol inthe presence of anhydrous sodium carbonate to give5,5-dimethyl-10-hydroxy-8-(3- methyl 2octyl)-3-{4-[1-(B-trifiuoromethylphenyl)-1-butenyl]}-5H-[1]benzopyrano[3,4-c]piperidine.

EXAMPLE 41 17 phenyl-2-propynyl) 5H [1]benzopyrano[3,4-c] piperidine.

EXAMPLE 42 3-benzyl-8-hydroxy-IO-methyl-S-oxo-l,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c] pyridine is obtained by reaction of1-benzyl-3-carbethoxy-4 piperidone with S methylresorcinol according tothe procedure described above in Example S-A.

EXAMPLE 43 8-hydroxy-lO-methyl-S-oxo-l,2,3,4-tetrahydro-5H [1]benzopyrano[3,4 c]pyridine is prepared by catalytic debenzylation of 3benzyl-8-hydroxy-IO-methyl-S-oxo- 1,2,3,4 tetrahydro5H-[1Jbenzopyrano[3,4-c]pyridine according to the procedure describedabove in Example 5-B.

EXAMPLE 44 8-hydroxy-5 ,5 lO-trimethyl-l,2,3,4-tetrahydro SH- 1]benzopyrano[3,4 c]pyridine is prepared by reacting 8- hydroxy 1O methylS-oxo-1,2,3,4-tetrahydro-5H-[1] benzopyrano[3,4 c]pyridine with methylmagnesium iodide according to the procedure described above in Example6.

EXAMPLE 45 8 hydroxy-3,5,5,IO-tetramethyl-l,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridine is prepared by reaction of 8-hydroxy 10methyl-5,5-dimethyl-1,2,3,4-tetrahydro- 5H-[1]benzopyrano[3,4-c]pyridinewith methyl bromide in the presence of anhydrous sodium carbonateaccording to the procedure described above in Example 3.

EXAMPLE 46 3-benzyl-8-hydroxy-5,5,10 trimethyl 1,2,3,4tetrahydro-SH-[1]bcnzopyrano[3,4-c]pyridine is prepared by reacting3-benzyl-8-hydroxy-lO-methyl-S-oxo-1,2,3,4-tetrahydr-5H-[1]benzopyrano[3,4c] pyridine with methyl magnesium bromide in anisole according to theprocedure described above in Example 6.

EXAMPLE 47 8-hydroxy-10-methyl-5,5-dihexy1 1,2,3,4 tetrahydro- SH- 1benzopyrano 3,4-c] pyridine is prepared by reactin g8-hydroxy-10-methyl-5-oxo-1,2,3 ,4-tetrahydro-H- 1]benzopyrano[3,4-c1pyridine with n-hexyl magnesium bromide according tothe procedure described above in Example 6.

EXAMPLE 48 3-cinnamyl-8-hydroxy-5,5,10-trimethy1 1,2,3,4 tetrahydro-SH[1]benzopyrano[3,4-c1pyridine is prepared by reacting 8 hydroxy5,5,IO-trimethyl-1,2,3,4-tetrahydro- 5H [1]benzopyrano[3,4-c1pyridinewith cinnamyl chloride in the presence of anhydrous sodium carbonateaccording to the procedure described above in Example 3.

EXAMPLE 49 3 acetyl 8hydroxy-5,5,10-trimethyl-1,2,3,4-tetrahydro-SH-[l]benzopyrano[3,4-c]pyridineis prepared by reacting 8 hydroxy-5,5,lO-trimethyl-1,2,3,4-tetrahydro-5H [1]benzopyrano[3,4-c]pyridine with an equimolar amount of acetylchloride in a benzene solution and in the presence of triethylamineaccording to the procedure described above in Example 10.

EXAMPLE 50 3-phenylacetyl-8-hydroxy 5,5,10 trimethyl-1,2,3,4- tetrahydro5H [1]benzopyrano[3,4-c]pyridine is prepared by reacting 8hydroxy-5,5,10-trimethyl-1,2,3,4- tetrahydro-SH- 1]benzopyrano 3,4-c]pyridine with phenylacetyl chloride in a benzene solution and in thepresence of pyridine according to the procedure described above inExample 11. V

18 EXAMPLE 51 3-(Z-phenylethyl)-8-hydroxy-5,5,IO-trimethyl 1,2,3,4-tetrahydro-SH- 1 benzopyrano[3,4-c] pyridine is prepared by reacting 3phenylacetyl-8-hydroxy-5,5,IO-trimethyl- 1,2,3,4tetrahydro-5H-[1]benzopyrano[3,4 c]pyridine with lithium aluminumhydride in a tetrahydrofuran solution according to the proceduredescribed above in Example 12.

EXAMPLE 52 3-[2-(4-methylpheny1)ethyl] 8 hydroxy-5,5,lO-trimethyl1,2,3,4-tetrahydro 5H [1]benzopyrano[3,4-c] pyridine is prepared byreacting 8-hydroxy-5,5,10-trimethyl 1,2,3,4 tetrahydro 5H[1]benzopyrano[3,4c] pyridine with 2-(4-methylphenyl)ethyl bromide inabsolute ethanol in the presence of anhydrous sodium carbonate accordingto the procedure described above in Example 3.

EXAMPLE 53 3 [3 (3,4 dimethoxyphenyl)propyl] 8 hydroxy- 5,5,10-trimethyl1,2,3,4 tetrahydro-5H-[1]benzopyrano [3,4-c]pyridine is prepared byreacting 8-hydroxy-5,5,10- trimethyl l,2,3,4tetrahydro-5H-[1]benzopyrano[3,4-c] pyridine with3-(3,4-dimethoxyphenyl)propyl bromide in absolute ethanol in thepresence of anhydrous sodium carbonate according to the proceduredescribed above in Example 3.

EXAMPLE 54 3 [l (2,4,6 tribromophenyl)ethyl]-8-hydroxy-5,5,10-trimethyl-1,2,3,4 tetrahydro 5H [11benzopyrano [3,4-c1pyridine isprepared by reacting 8-hydroxy-5,5,10- trimethyl 1,2,3,4 tetrahydro 5H[1]benzopyrano [3,4-c]pyridine with 1-(2,4,6 tribromophenyD-ethylbromide in absolute ethanol in the presence of anhydrous sodiumcarbonate according to the procedure described above in Example 3.

EXAMPLE 55 3[4-(4-nitrophenyl)butyl] 8hydroxy-5,5,10-trimethyl-1,2,3,4-tetrahydro 5H[1]benzopyrano[3,4-c]pyridine is prepared by reacting 8-hydroxy 5,5,10trimethyl- 1,2,3,4 tetrahydro 5H-[1]benzopyrano[3,4-c]pyridine with4-(4-nitrophenyl)butyl bromide in absolute ethanol in the presence ofanhydrous sodium carbonate according to the procedure described above inExample 3.

EXAMPLE 5 6 3 {3 [1 (3,4 methylenedioxyphenyl)-1-butenyl]}- S-hydroxy5,5,10 trimethyl 1,2,3,4 tetrahydro-SH- [1]benzopyrano[3,4-c]pyridine isprepared by reacting 8- hydroxy 5,5,10 trimethyl 1,2,3,4tetrahydro-SH-[l] benzopyrano[3,4-c1pyridine with 3-[1-(3,4methylenedioxyphenyl) 1 butenyl] bromide in absolute ethanol in thepresence of anhydrous sodium carbonate according to the proceduredescribed above in Example 3.

EXAMPLE 58 3 {3 [1 (4 acetylaminophenyl)-1-butenyl]}-8-hydroxy 5,5,10trimethyl 1,2,3,4 tetrahydro-SH-[l] benzopyrano[3,4-c]pyridine isprepared by reacting 8-hydroxy 5,5,10 trimethyl-1,2,3,4-tetrahydro 5H[1] benzopyrano[3,4-c]pyridine with 3-[1-(4 acetylaminophenyD-I-butenyl]bromide in absolute ethanol in the presence of anhydrous sodiumcarbonate according to the procedure described above in Example 3.

1 9 EXAMPLE 59 3 {4 [1 (3 trifiuoromethylphenyl)-1-butenyl]}-8- hydroxy5,5,10 trimethyl 1,2,3,4 tetrahydro-SH-[l] benzopyrano[3,4-c]pyridine isprepared by reacting 8-hydroxy 5,5,10 trimethyl 1,2,3,4tetrahydro-SH-[l] benzopyrano[3,4-c]pyridine with4-[1-(3-trifiuoromethylphenyl)-l-butenyljbromide in absolute ethanol inthe presence of anhydrous sodium carbonate according to the proceduredescribed above in Example 3.

EXAMPLE 60 3-cyclopropylcarbony1 8 hydroxy 5,5,10 trimethyl- 1,2,3,4tetrahydro 5H [l]benzopyrano[3,4-c] pyridine is prepared by reacting8-hydroxy-5,5,10-trimethyl-1,2,3,4- tetrahydro 5H [1]benzopyrano[3,4-c]pyridine with cyclopropylcarbonyl chloride in a benzene solution and inthe presence of pyridine according to the procedure described above inExample 21.

EXAMPLE 61 3-cyclopropylmethyl 8 hydroxy 5,5,10 trimethyl- 1,2,3,4tetrahydro 5H [1]benz0pyrano[3,4-c] pyridine is prepared by reducing3-cyclopropylcarbonyl-8-hydroxy- 5,5,l-trimethyl 1,2,3,4tetrahydro-H-[1]benzopyrano [3,4-c] pyridine with lithium aluminumhydride according to the procedure described above in Example 22.

EXAMPLE 62 3 (3 phenyl 2 propynyl)-8-hydroxy-5,5,l0-trimethyl 1,2,3,4tetrahydro 5H [1]benzopyrano[3,4- c]pyridine is prepared by reacting8-hydroxy-5,5,lO-trimethyl-l,2,3,4-tetrahydro 5H [1]benzopyrano[3,4-c]pyridine with 3-phenyl-2-propynyl bromide in absolute ethanol in thepresence of anhydrous sodium carbonate according to the proceduredescribed above in Example 3.

EXAMPLE 63 3-allyl 8 hydroxy 5,5,10 trimethyl-1,2,3,4-tetrahydro 5H[1]benzopyrano[3,4-c]pyridine is prepared by reacting8-hydroxy-5,5,IO-trimethyl 1,2,3,4 tetrahydro- SI-I[l]benzopyrano[3,4-c] pyridine with 3-bromo-1-pr0- pene in absoluteethanol in the presence of anhydrous sodium carbonate according to theprocedure described above in Example 3.

EXAMPLE 64 3-(2-propynyl) 8 hydroxy 5,5,10 trimethyl-1,2,3,4 tetrahydro5H [l]benzopyrano[3,4-c]pyridine is prepared by reacting 8-hydroxy5,5,10 trimethyl 1,2,3,4- tetrahydro-SH- 1 benzopyrano[3,4-c] pyridinewith 3-bromo-l-propyne in absolute ethanol in the presence of anhydroussodium carbonate according to the procedure described above in Example2-D.

EXAMPLE 65 3-(trans 3 chloroallyl) 8 hydroxy 5,5,10 trimethyl 1,2,3,4tetrahydro 5H [1]benzopyrano[3,4- c]pyridine is prepared by reacting8-hydroxy-5,5,10-trimethyl 1,2,3,4 tetrahydro 5H [1]benzopyrano[3,4-c]pyridine with trans-1,3-dichloro 1 propyne in absolute ethanol in thepresence of anhydrous sodium carbonate according to the proceduredescribed above in Example 4.

EXAMPLE 66 8 acetoxy 3,5,5,1O tetramethyl 1,2,3,4 tetrahydro- SH[1]benzopyrano[3,4 c]pyridine is prepared by reacting 8 hydroxy 3,5,5,1Otetramethyl 1,2,3,4- tetrahydro 5H [1]benzopyrano[3,4 c]pyridine Withacetic anhydride according to the procedure described above in Example24.

EXAMPLE 67 8 methoxy 3,5,5,10 tetramethyl 1,2,3,4 tetrahydro 5H[l]benzopyrano[3,4-c]pyridine is prepared by reacting 8 hydroxy 3,5,5,10tetramethyl 1,2,3,4-

tetrahydro 5H [l]benzopyrano[3,4 c]pyridine with methyl iodide in thepresence of sodium ethoxide according to the procedure described abovein Example 25.

EXAMPLE 68 8 carbamyloxy 3,5,5,10 tetramethyl 1,2,3,4 tetrahydro 5H [1]benzopyrano[3,4 c] pyridine is prepared by reacting 8 hydroxy 3,5,5,10tetramethyl 1,2, 3,4 tetrahydro 5H [1]benzopyrano[3,4 c] pyridine withan equimolar amount of phosgene in the presence of dimethylaniline, andreacting the resulting chloroformate With liquid ammonia according tothe procedure described above in Example 26.

EXAMPLE 69 8 (N methylcarbamyloxy) 3,5,5,10 tetramethyl- 1,2,3,4tetrahydro 5H [1]benzopyrano[3,4 c]pyridine is prepared by reacting 8hydroxy 3,5,5,l0 tetramethyl 1,2,3,4 tetrahydro 5H [l]benzopyrano[3,4c]pyridine With an equimolar amount of phosgene in the presence ofdimethylaniline, and reacting the resulting chloroformate withmethylamine according to the proce dure described above in Example 27.

EXAMPLE 7O 8 (N,N dimethylcarbamyloxy) 3,5,5,10 tetramethyl 1,2,3,4tetrahydro 5H [1]benzopyrano[3,4- c]pyridine is prepared by reacting 8hydroxy 3,5,5,10 tetramethyl 1,2,3,4 tetrahydro 5H [1]benzopyrano [3,4c]pyridine with an equimolar amount of phosgene in the presence ofdimethylaniline, and reacting the resulting chloroformate withdimethylamine according to the procedure described above in Example 28.

EXAMPLE 71 8 phosphonyloxy 3,5,5,10 tetramethyl 1,23,4- tetrahydro 5H[l]benzopyrano[3,4 c]pyridine is prepared by reacting 8 hydroxy 3,5,5,l0tetra-methyl- 1,2,3,4 tetrahydro 5H [l]benzopyran0[3,4 c]pyridine withone molar amount of phosphorus oxychloride in toluene in the presence ofpyridine, and reacting the resulting dichlorophosphinate with aqueouspotassium carbonate according to the procedure described above inExample 29.

EXAMPLE 72 By reducing the compounds of Examples 44-71 with hydrogenover a Raney nickel catalyst, following the procedure described above inExample 30, there can be obtained the following respective compounds ofFormula IIb:

(A) 8 hydroxy 5,5,10 trimethyl 5H [1]benzopyrano[3,4 c]piperidine.

(B) 8 hydroxy 3,5,5,l0 tetramethyl 5H [l] benzopyrano [3,4-c1piperidine.

(C) 3 benzyl 8 hydroxy 5,5,10 trimethyl 5H- [1]benzopyrano 3,4-c]piperidine.

(D) 8 hydroxy 10 methyl 5,5 dihexyl 5H [1] benzopyrano[ 3,4-c]piperidine.

(E) 3- cinnamyl 8 hydroxy 5,5,10 trimethyl-5H-[1]benzopyrano[3,4-c1piperidine.

(F) 3 acetyl 8 hydroxy 5,5,10 trimethyl 5H- [l]benzopyrano [3 ,4-c]piperidine.

(G) 3 phenylacetyl 8 hydroxy 5,5,10 trimethyl- SH- 1]benzopyrano [3,4-c] piperdine.

(H) 3 (2 phenylethyl) 8 hydroxy 5,5,10 trimethyl-SH- 1 benzopyrano[ 3,4-c] piperidine.

(J) 3 [2 (4 methylphenyl)ethyl] 8 hydroxy- 5 ,5 1 O-trimethyl-S H- lbenzopyrano 3,4-c] piperidine.

(K) 3 [3 (3,4 dimethoxyphenyl)propyl] 8 hydroxy 5,5,10 trimethyl 5H[1]benzopyrano[3,4 c] piperidine.

(L) 3 [1 (2,4,6 tribromophenyl)ethyl] 8 hydroxy 5,5,10 trimethyl 5H[1]benzopyrano[3,4 c] piperidine.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,514,464 May 26, 1970 Harry G. Pars et a1.

It is certified that error appears in the above identified patent andthat said Letters Patent are hereby corrected as shown below:

, should appear as shown below:

Column 21, the formula in claim 1 R 'N OH Signed and sealed this 23rdday of February 1971.

(SEAL) Attest:

WILLIAM E. SCHUYLER, JR.

Edward M. Fletcher, Jr.

Commissioner of Patents Attesting Officer

